Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.
Molecular pharmacology January 1, 2003 Barbara J Ebersole, Irache Visiers, Harel Weinstein et al. 72 citations
Indole agonists at the human serotonin 5-HT2A receptor achieve differing efficacies through specific hydrogen-bond interactions with serine residues in helices 3 and 5. Serotonin forms hydrogen bonds with Ser3.36 and Ser5.46; methyl-substitution of the cationic primary amine or the backbone N1-amine disrupts these bonds and reduces efficacy. Mutating Ser3.36 to alanine largely eliminates efficacy differences caused by cationic amine substitution, while mutating Ser5.46 to alanine reduces the efficacy loss from N1-amine substitution. Computational modeling shows these interactions shift the agonist's position in the binding pocket, and the indole ring's position correlates with agonist activity. The findings support a mechanism where agonist position, influenced by specific helix interactions, determines receptor activation, likely shared by other class A G-protein coupled receptors.